Trial Information

Phase III Open Label Trial for Use of [18F]-Fluoro-Deoxy-Glucose (18F-FDG) in Positron Emission Tomography Imaging in Oncology

1.0 Background & Introduction

In general, diagnostic imaging can address two issues: structure and function. One can
either view structures in the body and image anatomy using structural imaging modalities
such as plain film radiography (X-ray), Computerized Tomography (CT) and Magnetic Resonance
Imaging (MRI), or one can view chemical processes and image biochemistry and function using
biochemical imaging modalities such as Planar and Single Photon Emission Computerized
Tomography (SPECT) imaging and Positron Emission Tomography (PET). The strength of the
biochemical imaging methods is in distinguishing tissues according to metabolism rather than
structure.

18F-Fluorodeoxyglucose (FDG) is the most commonly used tracer for PET imaging; its use and
safety are well established world wide. The 18F-FDG is injected intravenously and is
transported from blood to tissues in a manner similar to glucose. It has been understood
for over 5o years, that cancer cells, in general, have increased glucose uptake and
anaerobic metabolism compared to normal tissues. Like glucose, FDG is taken up into cells
through glucose transport proteins (GLUT) and then phosphorylated by hexokinase to
FDG-6-phosphate. However, since FDG-6-phosphate is not a substrate for subsequent glucose
metabolic pathways and has a very low membrane permeability, the FDG-6-phosphate becomes
trapped in tissue in proportion to the rate of glycolysis. This accumulation of
18F-FDG-6-phosphate forms the basis of tumor metabolic imaging with PET.

2.0 Indications

Cancer treatment and outcome depend largely on the accurate diagnosis and staging of
disease. There is extensive data in the literature indicating the importance of PET imaging
in accurately characterizing disease, determining stage and sites of recurrent disease in
many cancer types. For these indications, it is well documented in the literature that
functional imaging with PET exceeds sensitivity, specificity and accuracy of conventional
3-D imaging modalities. The most widely cited reference for the efficacy of PET imaging is:
A Tabulated Summary of the FDG PET Literature, published by Gambhir et al, JNM (2001) 42:
1S-93S. In this study the average FDG PET sensitivity and specificity across all oncology
applications are estimated at 84% (based on 18,402 patient studies) and 88% (based on 14,264
patient studies), respectively. The average management change across all applications is
estimated to be 30% (based on 5,062 patients). Data was obtained combining 419 total
articles and abstracts on studies in which FDG PET was used. Various methods of analysis
were applied to these data, which revealed only a small amount of variation in the ratio
values. Specifically, the sensitivity of PET ranged from 84 - 87%, the specificity ranged
from 88% - 93%, and the accuracy ranged from 87 - 90%.

In the United States, the Food and Drug Administration (FDA) has approved 18F-FDG for use in
all cancer types. On January 28, 2005 the Centers for Medicare and Medicaid Services (CMS)
announced that it would reimburse PET imaging studies when performed for almost all
previously non-covered oncology indications. All previous PET coverage remained fully in
effect, and initial staging of cervical cancer was added without conditions but coverage was
expanded conditionally to include all cancers and non-covered indications except breast
cancer diagnosis and regional lymph node staging.

(http://www.cms.hhs.gov/mcd/viewncd.asp?ncd_id=220.6.15&ncd_version=1&basket=ncd%3A220%2E6%2E15%3A1%3APET+%28FDG%29+for+All+Other+Cancer+Indications+Not+Previously+Specified)

The indication for performing this diagnostic imaging test is the need for non-invasive,
functional assessment of patients suspected of having or previously diagnosed with:

- Lymphoma

- Colorectal cancer

- Breast cancer

- Esophageal cancer

- Head & neck cancer

- Melanoma

- Brain tumors

- Cervical cancer

- Testicular (Germ Cell) cancer

- Thyroid cancer

- Lung cancer

- Sarcoma

3.0 Study Objectives

Objectives of this study are to evaluate 18F-FDG PET as a decision making and diagnostic
tool in the management of oncology patients in British Columbia. With a population base of
over 4 million people, standardized cancer treatment protocols, and evidence-based
guidelines for PET imaging, the BCCA is positioned to make an important contribution to
defining the role of PET in the Canadian health care system.

4.0 Study Design

This will be a phase III open label study design in which additional safety data will be
collected from the first patient being scanned from each of the first three batches of
18F-FDG delivered to our clinical site. Data will be collected from referring physicians
with respect to how the PET scan results affected patient management and results of the PET
scan will be correlated with biopsy results when available. All subjects are informed of
anticipated effects (none) and purpose of the injected substance. There is no intent to
change the way this protocol is conducted or to in any way alter the effect or purpose of
the injected tracer. Subjects are approached with respect to their willingness to
participate in the proposed study based on clinical criteria and undergo a brief clinical
assessment followed by scanning as outlined below.

5.0 Study Time-Frame

The B.C. Cancer Agency anticipates a start date in June 2005 and a potential completion date
in August of 2007, at which time our on-site (Vancouver Cancer Centre) radiopharmacy and
cyclotron will be operational. Two years of data collection will provide meaningful numbers
for analysis and support of an 18F-FDG New Drug Submission (NDS) to Health Canada.

6.0 Patient Population and Sample Size

A total of 5,000 patients will be entered into the study. This number is based on the
anticipated number of PET scan referrals based on the criteria for study inclusion outlined
below and our clinical capacity of 12 to 14 patients per day operating 220 days per year.
This will be the only publicly funded PET program in the province of British Columbia. A
sample size of 5,000 patients will allow the PET program in BC to operate until Phase B of
the Functional Imaging Program is implemented and the BCCA is positioned to submit an NDS
for 18F-FDG.

Assuming a response rate of 90% to the patient management survey and a change in patient
management for 30% of the study participants, precision for the 95% confidence interval of
the estimated proportion will be .013. Given the same response rate and change in patient
management proportion, a tumour site with 100 patients will yield a precision of .089 for
its 95% confidence interval.

A sensitivity (or specificity or accuracy) rate of 80% can be estimated for the full sample
with a precision of .011 for its 95% confidence interval, or a precision of .080 for a
sub-sample of 100.

Additional safety data will be collected from the first patient imaged from each of the
first three batches of FDG delivered to our clinical site (N=3). The chemical structure of
our product is identical to authentic FDG. We have performed a minimum of five consecutive
18F-FDG productions with all quality control passing and will have done many more in the
course of this CTA review process. The safety record of FDG PET worldwide is undisputable
and we expect the number of adverse events in our study to be zero. In addition to baseline
assessment, these subjects will have their blood pressure, oxygen saturation, heart rate and
temperature monitored every 15 minutes for 2 hours post-procedure. Patients will be
questioned as to their general well-being after the scan. If there are concerns that the
patients' health status has changed during or immediately following the scan, then a
physician will provide a more detailed assessment. Each of these three patients will be
followed up by telephone, usually the day after the scan to help insure there were no
delayed effects. These whole body PET scan images will be reviewed independently by two
Nuclear Medicine physicians to confirm an expected biodistribution of radioactivity. If a
subject did experience a reaction post-injection that could not immediately be attributed to
another condition or exposure, or if the biodistribution of FDG in normal tissue was altered
and could not be explained on clinical grounds (eg. patient on G-CSF), the tracer would be
re-examined and tested for impurities and pyrogens. The safety data collected from these
three patients will verify that the FDG produced by the BCCA is behaving as expected.

Patients considered appropriate for participation in this protocol are drawn from a
population made up of the following parameters:

- Patients are between the ages of 19 and 90 years, although exceptions to these
numbers may be made depending on the individual's ability to understand, give
assent/consent, and tolerate the procedure. Health Canada can expect a separate CTA
submission from the BCCA within the next few months for FDG-PET indications in the
pediatric oncology population.

- Patients are both female and male and of any race with no preference for any group over
another.

- Patients are those who are suspected of having or who have been previously diagnosed
with cancer and meet BCCA evidence-based guidelines for FDG-PET.

7.0 Inclusion Criteria

- Must be a resident of British Columbia, Canada

- Age 19 years or older.

- ECOG performance status 0 - 3.

- Able to provide written informed consent.

- Referred by a treating physician.

- Must meet BCCA Evidence-Based guidelines for FDG-PET in Oncology

- Patients must be able to tolerate the physical/logistical requirements of completing a
PET scan including lying flat for up to 45 minutes and tolerating intravenous
cannulation for injection.

8.0 Exclusion Criteria

- Patients' blood glucose > 11.1 mmol/L (200 mg/dL) measured by glucometer immediately
prior to scan.

- Pregnancy.

- Patients unable to provide informed consent.

- Patients who are medically unstable eg. acute cardiac or respiratory distress,
hypotensive

- Patients who exceed the safe weight limit of the PET/CT bed (204.5 kg) or who cannot
fit through the PET/CT bore (diameter 70 cm).